DE60224832T2 - TOBACCO AND / OR TOBACCO IN COMBINATION WITH TOBACCO SUBSTITUTE COMPOSITION FOR USE AS A BUTCH IN THE MOUTH VALVE - Google Patents

Abstract

A novel composition for the use as snuff in the oral cavity, the composition comprising tobacco and/or a tobacco substitute encapsulated in a membrane material comprising one or more membranes at least one of which being water permeable and water-insoluble. A novel composition enables a selective release of e.g. nicotine while it at the same time reduces the release of substances, which normally lead to unwanted side effects. The novel compositions may be used as a healthier alternative to snuff and other tobacco products such as, e.g., cigarettes, cigars and pipe. Methods for giving up smoking, reducing nicotine craving, reducing side effects normally related to smoking and snuffing of tobacco as welt a method for the preparation of a composition according to the invention.

Description

Field of the invention

The The present invention relates to a novel composition for use as snuff in the oral cavity, wherein the composition tobacco and / or tobacco in combination with a tobacco substitute, which is encapsulated in a membrane material containing one or more Includes membranes, at least one of which permeable to water and insoluble in water is. The new composition allows for selective release from Z. B. nicotine while It also reduces the release of substances that normally too unwanted Cause side effects. The new compositions can as healthier Alternative to snuff and other tobacco products, such as cigarettes, cigars and whistle, to be used.

The The invention also relates to methods of cessation smoking, to reduce nicotine addiction, to reduce Side effects that usually accompany smoking and runny nose of tobacco, as well as a method of preparation a composition according to the invention.

Background of the invention

The Use of tobacco is in a large part of the world population deeply rooted. In the Scandinavian countries and especially in Sweden is the use of wet snuff (snus) as an alternative very common for smoking. Snuff is fermented and ground / minced tobacco with a relatively large one Water content (40-60 % By weight), which is usually under the fore upper lip of a human should be used.

tobacco itself varies slightly in nicotine content due to its natural Origin. To stop nicotine release in wet snuff can various buffer systems, eg. As carbonates, are added. Of the moist snuff is either loose, as a mass in a box or in the form of individual cans packed in small nonwoven bags. A number of filled and sealed bag is then packed in a box.

Of the moist snuff in the form of a single dose is due the ease of use, compared to the bulk, has become popular. The popularity from wet snuff is very likely to be pharmacological Attributed nicotine absorption profile. The Nicotine dose and the absorption rate are about 10 ng per ml during 10 mins. The plasma nicotine concentrations In the first few minutes of using the snuff you will rise quickly and reach levels that are comparable to those which smoking cigarettes within 30 minutes to be obtained. Measurements of plasma nicotine concentrations after a single day of consumption of wet snuff also levels similar to those of the cigarette application.

The Kinetics are a bit slower compared to the kinetics of smoking of tobacco, such as cigarettes and cigars, however, is the total amount of adsorbed nicotine higher, if snuff is used.

As the daily Use of cigarettes, cigars, pipes and other smoking products burdened the daily Application of snuff the body the user with a number of harmful connections in the Tobacco are present.

Of the Disadvantage of snuff is the large number of connections, the for the body more or less harmful are, for. B. different tobacco-specific nitrosamines, the Represent compounds that are known to cause various diseases cause such as gastrointestinal disorders and cancer.

Various Tobacco products and / or devices for tobacco products are in the Literature already known, where the user the desired Effect of nicotine, but at the same time the harmful ones Avoid substances that are released from the tobacco.

in the U.S. Patent 4,848,376 For example, an inhaler is presented in which the tobacco is more or less used in the form of a cigarette and nicotine is released due to elevated temperatures, although below the combustion temperature of tobacco.

The U.S. Patent 4,141,269 describes a method of inhaling nicotine from tobacco without burning the tobacco.

One another way to avoid the harmful substances that are in the Tobacco is the replacement of tobacco with nicotine.

in the U.S. Patent 4,655,231 An artificial dry snuff containing nicotine is proposed. The snuff, which consists of pure nicotine salts and drug carriers, z. As powdery organic sugars, there is, the nasal mucosa should be administered. This is a medical nasal composition that is not based on natural tobacco.

Various Devices have also been designed to deliver nicotine from a tobacco composition, in the oral cavity is arranged.

The U.S. Patent 5,346,734 describes a perforated latex oral bag for loose wet snuff, the bag acting as a barrier to prevent direct physical contact between the tobacco product and the gum. The bag must be filled by the user, cut so that it fits into the oral cavity of the user, and is reusable.

The US Patent 6,162,516 describes a shield that must also be filled with snuff by the user, the shield acting as a barrier to reduce tobacco contact with the delicate inner cheek lining and gum surfaces when snuff is used.

Both that U.S. Patent 5,346,734 as well as that US Patent 6,162,516 provide the user with a protection device to avoid direct contact of the tobacco fibers in the snuff with the oral tissues, however, no measures are taken to prevent or reduce the release of potentially harmful and undesirable substances. Thus, even harmful and undesirable substances may be released from the tobacco in the oral cavity.

None The above documents have solved the problems that eliminating or Delay the release of unwanted and harmful Substances in the oral cavity concern when a tobacco-containing product as a snuff is used. There is still a need for the development of Tobacco-containing Products that are not unwanted and harmful Release substances to the body after use.

Disclosure of the invention

Accordingly, presents the present invention provides a composition in which the Release of nicotine from snuff can be freely designed even if the release of unwanted and harmful Substances from the tobacco is dramatically reduced.

Consequently The present invention provides a composition for use in the oral cavity ready, comprising tobacco and / or tobacco in combination with a Tobacco substitute encapsulated in a membrane material, the one or more membranes, at least one of which permeable to water and insoluble in water is.

The Essential of the invention is the use of a membrane mate rials, that makes it possible Nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof in a predetermined manner and simultaneously the properties of retention the substances that are undesirable, to such an extent that has side effects that are normally associated with The use of snuff in the oral cavity can be observed dramatically are reduced.

tobacco

The tobacco used in the new snuff composition according to the invention may be natural tobacco leaves to maintain the authentic taste and feel of tobacco. The tobacco plant belongs to the family Solanaceae and the genus Nicotiana. There are more than 60 species of tobacco, with Nicotiana tabacum and Nicotiana rustica being the most commonly used for smoking or snuffing tobacco products. For the production of moist snuff bak, the tobacco, which typically has a nicotine content of about 1% to 8%, is dried, ground and mixed with a fermentation solution. The mixture is then typically fermented at elevated temperature for 5 days to 4 weeks. Thereafter, the tobacco mass with a suitable buffer such. B. carbonate is mixed so that a pH of about 6 to 8 is obtained for the wet snuff mixture to allow and enhance the release of nicotine or a derivative thereof from the tobacco. The water content in the final product may range from about 10% to about 60%.

To the wet snuff can additional Compounds, such. B. sweeteners, Flavorings and other flavor additives, detergents and preservatives, Release modifiers and other liquids, such as oil, organic solvent and plant extracts.

In another embodiment of the invention of course partially replaced with a tobacco substitute, fermented tobacco, such as As nicotine and / or a nicotine derivative, analog, salt, solvate or a mixture thereof, selected from the group those of nornicotine, lobeline, methylanabasine, anabaine, nicotine hydrochloride, Nicotine dihydrochloride, nicotine sulfate, nicotine monotartrate, nicotine hydrogen tartrate, Nicotinic salicylate or nicotinic acid chloride monohydrate. To keep of the same feeling, like when a wet snuff product is in the oral cavity can, can some extra fillers, such as B. nondigestible fibers are added.

Independently of, whether natural Tobacco and / or tobacco in combination with a tobacco substitute for the new one Snuff composition can be used, the tobacco and / or the tobacco substitute preferably has a content of nicotine and / or a Nicotine derivative, analog, salt, solvate or a mixture thereof from about 0 wt .-% to about 30 wt .-%, such as. B. about 0.5 From about 0% to about 25% by weight, from about 0.1% to about 20%, by weight, for example From 0.1% to about 15% by weight, from about 0.1% to about 10% by weight, from about 0.1% to about 9%, or about 0.1% to about, by weight 8% by weight.

membrane material

According to the invention is the tobacco and / or tobacco substitute in a membrane material locked in. The membrane material may be one or more membranes include. As used herein, the term "membrane" describes a thin polymeric film. the natural one Having pores and acts as a selective permeability barrier layer. The expression closes no material made of paper or polymeric materials one in which not natural occurring openings were formed.

At least one of the membranes may be water insoluble to spread of the snuff in the oral cavity to prevent and the beneficial properties of the selective Membrane material during the Application, in terms of retention of unwanted Substances.

At least one of the membranes can be water permeable to diffuse of water in the encapsulated tobacco and / or the encapsulated To enable tobacco substitute and to allow that z. B. nicotine through the polymeric membrane material diffused and thus for the absorption available becomes.

The Membranes can from a predominantly hydrophilic or hydrophobic nature. The hydrophilic or hydrophobic The nature of the membrane has an effect on the release of substances such as B. nicotine through the membrane, since the flow of substances through the Membrane of the ability the membrane for hydration, z. B. the formation of hydro channels the membrane depends. These hydro channels are a requirement for the molecular transport when using dry polymeric membranes become. In general, the flow is of hydrophilic substances by a hydrophobic membrane, compared to a hydrophilic membrane Membrane, slower. This is probably due to the lower sources attributed to the pores of the hydrophobic membrane, d. H. in the hydrophobic Membranes, the nicotine diffusion takes place well organized polymeric material and hydrophobically organized Water.

A or more of the membranes used to make the composition can be used a synthetic or semi-synthetic membrane. below are some examples of natural, synthetic and semi-synthetic, Hydrophilic and hydrophobic membranes specified in the new Snuff composition according to the invention can be used.

Examples of membranes are membranes of cellulose acetate and derivatives thereof, carboxymethylcellulose membranes, polycellulose ester membranes, other cellulose derivatives such as ethylcellulose, propylcellulose, polyethylene membranes, polypropylene membranes, polystyrene membranes, Polyvi nylchloride membranes, polyvinyl acetate membranes, membranes made from polymers of methacrylates and acrylates, natural rubber membranes, polycarbonate membranes, polyethylene terephthalate membranes, polyester membranes, polyamide membranes and nylon membranes.

At least the outer membrane in the membrane material including the tobacco and / or tobacco substitute from a biocompatible and physiologically acceptable polymeric material, since the new snuff composition near the mucosa or in contact with the same at the mouth level while the use must be arranged.

moreover At least one of the membranes in a membrane material surface treatment with z. B. Polycarbophilen be subjected to a biological adhesiveness to get the new snuff composition in the oral cavity.

The Molar mass threshold of the membrane material used in the new snuff composition can be varied so that a desired release of nicotine and other substances through the membrane material. The molecular weight threshold of a membrane is the smallest in molecular weight molecule, of which 90% can not penetrate the membrane, defined. In addition to Molecular weight hangs the exact permeability of a molecule the shape, the degree of hydration and the charge of the molecule.

At least one of the membranes comprising the membrane material may be a Mol mass threshold of about 500 to about 40 000 have such. B. about 500 to about 5000, about 800 to about 4000, about 1000 to about 3500 or about 2,000 to about 40,000, about 3,000 to about 30,000, about 5,000 to about 25,000, about 7,500 to about 20,000, or about 10 000 to about 20,000.

The Release of nicotine and / or other substances by the membrane material also depends on the thickness of the membrane material. The diffusion process of molecules through the membrane decreases as the membrane thickness increases and vice versa. Thus, the thickness of the membrane material in terms of obtaining a desired one Release of nicotine and other substances by the membrane material be varied.

The lower limit for the thickness of the membrane material is determined by which thickness from a practical point of view is possible and the upper value is limited by which thickness is a comfortable one Adaptation of the new snuff composition in the oral cavity of the User allows.

Accordingly, at least one of the membranes making up the membrane material has a thickness of 2 to about 200 microns have, such. About 5 to about 100 microns, about 7.5 to about 50 microns, about 7.5 up to about 40 μm, about 7.5 to about 35 μm, about 7.5 to about 30 microns or about 7.5 to about 25 μm.

release profiles

In order to The new snuff composition will produce an effect that will need nicotine or a nicotine derivative, analog, salt, solvate or mixture of which, selected from the group consisting of nornicotine, lobeline, methylanabasine, anabasin, Nicotine hydrochloride, nicotine dihydrochloride, nicotine sulfate, nicotine monotartrate, Nicotinic acid tartrate, nicotinic salicylate or nicotinic acid chloride monohydrate, be released from the composition.

The Release profile can be in terms of speed and the Amount of nicotine and unwanted Substances released by the membrane are designed become.

The Release of nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof from the new snuff composition can be designed so that they are in sufficient quantity and / or a sufficient speed are released, a desired one To enable effect and, on the other hand, be designed to retain substances that normally cause side effects, such as Nitrosamines, and / or such substances in a very small amount and / or be released at a very low speed.

When Measure of selective release of nicotine and / or a nicotine derivative, analog, salt, solvolate or mixture thereof, the impurity index - IPI - was introduced.

Of the IPI is calculated from the UV spectra ranging from 200 nm to 900 nm recorded as described in Example 2, and he is as the relationship the sum of peak heights, which are different from those of nicotine (i.e., unwanted and harmful Include substances) to the peak height of nicotine. In other words, there is a lower IPI that's a big one Amount of nicotine, compared to the amount of unwanted Substances through which the membrane is released.

In a preferred embodiment of the invention the pollution index IPI is not more than 3.0, such as At most 2.75, at most 2.5, at most 2.0, at most 1.75, at most 1.5, at most 1.5 or at most 1.4 when measured after 90 minutes.

In an embodiment of the invention could the release profile of nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof of the invention e.g. B. fast and the release of nicotine from the commercially available moist snuff equivalent be while maintaining a low IPI value, i. H. the release of undesirable Substances is limited.

Furthermore For example, a composition of the invention may be designed so that they nicotine and / or a nicotine derivative, analog, salt, solvate or release mixture thereof in a controlled manner, such as. B. fast (faster than from the reference product incorporated herein) Examples), relatively fast (i.e., similar or almost similar the reference product used herein in the examples) is delayed (i.e. H. with a time delay, during which time no nicotine is released and subsequently nicotine is liberated), sustained or sustainable (ie a relative slower release than the reference product, around any peak concentration to avoid and maintain a relatively constant plasma nicotine concentration to get after the application).

In another embodiment The invention may include the release of nicotine or a nicotine derivative, -analogon, salt, solvate or mixture thereof be delayed, compared with the commercially available wet snuff, to the effect of nicotine replacement products, such as. Patches, to imitate.

The Release of nicotine or a nicotine derivative, analogue, salt, solvate or mixture thereof may be by the method described in Example 1 Release test can be determined, but other suitable Methods used to determine the release of nicotine d. H. the embodiments of the invention described below with reference to Example 1 are without the relevant release tests on the one in the Example 1 test should be limited.

The Tobacco composition and / or tobacco composition in conjunction with a tobacco substitute can be designed so that at least about 50% by weight of the total content of nicotine and / or a nicotine derivative, -analogon, salt, solvate or mixture thereof within a maximum of 60 minutes, if they follow the example below 1 release test is described.

In a further embodiment of the invention may be the tobacco and / or tobacco substitute composition be designed so that at most 25% by weight of the total content of nicotine and / or a nicotine derivative, -analogon, salt, solvate or mixture thereof within a maximum of 60 minutes, if they follow the example below 1 release test is described.

In a still other embodiment of the invention may be the tobacco and / or tobacco substitute composition be designed so that at least about 50 wt .-% of the total content nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof released within a maximum of 120 minutes when released according to the release test described in Example 1 below is subjected.

below follow release profiles for Compositions according to the invention. Release profiles are a function of weight percent of total nicotine released time, measured after 0, 3, 30, 90 and 180 minutes. The release profiles according to the invention shut down however, also profiles that come through just one or any combination described below, d. H. a release profile according to the invention could z. B. by the wt .-% of released nicotine after 3 minutes and 90 minutes or 3 and 90 and 180 minutes or 90 and 180 minutes or any combination be defined below.

A composition according to the invention is suitably designed to release nicotine and / or a nicotine derivative, analogue, salt, solvate or mixture thereof from the tobacco or tobacco in combination with the tobacco substitute according to the following characteristics: Time (min) released wt .-% of the total nicotine content 0 from about 0 to about 20, such as from about 0 to about 15, or from about 0 to about 10; 3 from about 0.5 to about 40, such as from about 0 to about 35, from about 0 to about 30, from about 0 to about 25, or from about 0 to about 20; 30 from about 2 to about 100, such as about 2 to about 90, about 2 to about 80, about 2 to about 70, about 2 to about 65, about 2 to about 60, about 5 to about 60, about 5 to about 55 , about 7.5 to about 55 or about 10 to about 50, to 100, 90 from about 10 to about 100, such as about 10 to about 95, about 15 to about 90, about 20 to about 90, about 25 to about 85, about 30 to about 80, about 35 to about 80, or about 4 to about 80; 180 from about 40 to about 100, such as from about 45 to about 100, from about 50 to about 100, from about 55 to about 100, from about 60 to about 100, from about 65 to about 100, or from about 70 to about 100; and the release is determined as described in Example 1.

In particular, a composition according to the invention releases nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof from the tobacco or tobacco in combination with a tobacco substitute according to the following release profile characteristics: Time (min) released wt .-% of the total nicotine content 0 from about 0 to about 15; 3 from about 1 to about 25; 30 about 7.5 to about 55; 90 about 35 to about 80; 180 from about 65 to about 100; and the release is determined as described in Example 1 herein.

In a further embodiment, a composition according to the invention releases nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof from the tobacco or tobacco in combination with a tobacco substitute according to the following release profile characteristics: Time (min) released wt .-% of the total nicotine content 0 from about 0 to about 10; 3 from about 1 to about 20; 30 from about 10 to about 50; 90 from about 40 to about 90; 180 from about 70 to about 100; and the release is determined as described in Example 1 herein.

In yet another embodiment, a composition according to the invention releases nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof from the tobacco or tobacco in combination with a tobacco substitute according to the following release profile characteristics: Time (min) released wt .-% of the total nicotine content 0 from about 0 to about 10; 3 from about 1 to about 20; 30 about 30 to about 50; 90 from about 65 to about 90, and the release is determined as described in Example 1 herein.

Design of the membrane material

 As described above the membrane material properties such as hydrophobicity, hydrophilicity, Molar mass threshold and membrane thickness, for designing a desired Release profile for Nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof.

in the Below are some examples of how membrane materials are designed can be. The examples are illustrative only Purposes and are not intended to limit the invention in any way.

A Multi-layer membrane is z. B. designed to be a membrane material contains which is hydrophilic and contains a second membrane material, the is lipophilic. Both membrane components are in such a Way selected, the membrane material has a molecular weight threshold which is sufficient so that the relatively small nicotine molecule is the same with ease can happen.

The amphiphilic nature of nicotine allows it that the same both hydrophilic and hydrophobic materials can happen while the main part of both the hydrophilic and the lipophilic, undesirable and harmful Substances can not penetrate the membrane material. Lots other combinations of different types of membranes are Naturally possible, and based on the present disclosure, one skilled in the art will appreciate Known to select the different membranes to ensure appropriate release to obtain.

One another example of a composition according to the invention is a composition in which the membrane material is a bilayer membrane wherein one membrane is preferably hydrophilic and the other Membrane predominantly is hydrophobic. Both membranes have a high permeability to nicotine, while a slight diffusion through aqueous Pores is maintained. The release profile of nicotine could either identical to the release profile of original snuff be or could be like that be designed to be a sustained or sustained release is present. The unwanted and harmful Substances from the tobacco should essentially be inside the membrane remain.

Shape and size of a composition according to the invention

A Composition according to the invention can all kinds Sizes and Reach shapes, such. Round, circular, oblong, elliptical, square, rectangular or trapezoidal. The selected shape and / or size may be such be that a comfortable fit in the oral cavity is made possible.

The Site of a composition according to the invention in the oral cavity may be in the middle or on the sides of it below the top Front lip, in the middle or on the sides of it below the lower front lip, under the tongue or in the cheeks.

Other aspects of the invention

In In other aspects, the invention also relates to use a composition according to the invention as a smoking substitute, and it can be used by people who suffer from nicotine addiction or who quit smoking or reduce it want. In such cases the content of tobacco and / or tobacco substitute is adjusted to the individual It is possible to design a kit that can Compositions according to the invention with different concentrations of tobacco and / or tobacco substitute includes. Such compositions in a kit could e.g. B. Compositions containing a decreasing content of tobacco or nicotine.

In In another aspect of the invention, it relates to a method for the preparation of a composition according to the invention.

The Details and the description relating to the compositional aspects apply equally also for other aspects of the invention.

Brief description of the drawings

1 Figure 11 shows the release profile of wet tobacco using side-by-side diffusion cells provided with special membranes having different physical properties.

2 shows the impurity index (IPI) for different hydrophilic membranes with different thicknesses and different molecular weight thresholds. The reference is filter paper.

3 shows the maximum nicotine flux as a function of membrane thickness for a hydrophilic membrane with a molecular weight threshold of 13,000. The reference flow illustrates the flow through filter paper.

The The following examples are intended to illustrate the invention without affecting the same to restrict.

Examples

example 1

Diffusion profiles of hydrophobic membranes and hydrophilic membranes having different physical properties

membranes, from regenerated cellulose acetate dialysis hoses with varying molecular weight threshold were made together with vinyl and polyethylene membranes of different thicknesses in terms of the diffusion profiles of nicotine released from tobacco tested through the membranes.

Diffusion chamber test

In a side-by-side diffusion chamber separated by a membrane is, 1 g snuff (SVENSKT SNUS, GOTHIATEK, General) was in aqueous PBS (phosphate-buffered saline according to Ph. Eu.) with a pH of 6.6 on the donor side of the membrane in the diffusion chamber arranged. In the receiver chamber PBS was placed at a pH of 6.6. The cells of the diffusion chamber were connected by connecting a water bath maintained at a temperature of 37 ° C ± 0.5 ° C. The temperature control was carried out around the environment of the oral cavity to simulate.

diffusion profiles were sampled from the receiver chamber 0, 3, 30, 60, 90, 120 (110 minutes for the polyethylene membrane) and 180 minutes after the start of the diffusion test constructed. The concentration of nicotine in the recipient's chamber was determined by HPLC using a C-18 column, 5 μm, size 4.5 mm x 15 cm, using a mobile phase consisting of 70 vol.% 0.1 M Phosphate buffer (pH 4.5), 30% acetonitrile and 2.3 g sodium dodecyl sulfate / l existed, at a flow rate of 1 ml / min and a temperature of 40 ° C. The sample volume was 10 μl and Detection was performed using a UV detector at 260 nm worked.

The The membranes used were regenerated cellulose acetate dialysis tubes with a varying molecular weight threshold and varying vinyl and polyethylene membranes Thickness.

When Reference became a piece Filter paper with an average pore size of 8.8 microns, the commercially used Nonwoven bag for Used to imitate snuff.

Reference filter paper

Table I shows a comparison of the release profile of nicotine for a commercial fiber puff bag for snuff and a piece of filter paper used as reference in the experiments. The measurements were made as described above and the results are the mean of 2 individual experiments. Table I: Comparison of nicotine release profile for a commercial nonwoven filter and a reference filter paper filter type released nicotine (mg / ml) 15 s 30 min 60 min 90 min Reference filter paper 11.5 64.4 92.0 202.4 commercial nonwoven filter 9.4 65.8 90.1 205.5

The Results of Table I show that the reference filter paper no barrier function to the transport of nicotine having.

Hydrophobic membranes

Hydrophobic membranes, e.g. Vinyl and polyethylene membranes, show a slower nicotine release profile compared to hydrophilic membranes (See 1 ). The slower profile is probably due to less swelling of the pores of the hydrophobic membrane, ie in the hydrophobic membranes, the diffusion of nicotine occurs through well organized polymeric material and hydro phobic organized water and not by watery pores.

In Table 2 below are the results of the one described above Indicated experiments.

Hydrophilic membranes

1 shows that the release of nicotine by a hydrophilic membrane of regenerated cellulose acetate dialysis tubing is high and close to nicotine release by the reference filter paper. 1 also shows that the physical properties, ie the molecular weight threshold and the thickness of the hydrophilic membrane, affect the permeability of nicotine, as indicated below.

A Membrane with a relatively small molecular weight threshold, z. B. one Molar mass threshold of 3500, often has a sigmoidal release profile for nicotine. In other words, a considerable one delay is expected before the nicotine begins to penetrate the membrane, even if the size of the nicotine molecule is significant smaller than the molecular mass threshold of 3500.

A Membrane with a higher Mol mass threshold, z. B. a molecular weight threshold of 13 000, seems but a release profile for Nicotine, which is very close to the nicotine release profile Reference filter paper is located.

This Difference may be due to the much lower aqueous motility of nicotine be due in the membrane with a molecular weight threshold of 3500, compared to the membrane with a molecular weight threshold of 13,000.

1 Figure 4 also shows that as the thickness of a membrane increases, the flow of nicotine through the membrane decreases.

example 1 shows that it is possible is to construct a polymeric membrane resulting in a release profile from nicotine out of wet tobacco through the membrane, the the release profile through a commercial nonwoven snuff pouch very similar is, d. H. in terms of the shape of the profile and the individual release dates (Time, percentage released). In particular, it seems so too be that a hydrophilic membrane material is suitable. In addition, that depends Release profile of the molecular weight threshold of the membrane, the thickness the membrane and the membrane material itself.

example Figure 1 also shows that some hydrophobic membranes, e.g. B. vinyl and Polyethylene membranes, a slower nicotine release profile, compared with the hydrophilic membranes.

• *gemessen nach 110 Minuten

All of these observations make it possible to construct membranes that allow specific release of nicotine, ie, it is possible to construct membranes having desirable release properties, e.g. As a fast or a slow release of nicotine depending on the purpose of the composition. In other words, the specific characteristics of a membrane or membrane material can be used to design a controlled and well-defined release profile for the release of nicotine from a composition according to the invention. Table 2: Release of nicotine from membranes of various types, thicknesses and pore sizes membrane Release of nicotine (%) 0 min 3 min 30 min 90 min 120 min 180 min Reference filter (original) 4.7 18.7 46.5 80.8 88.8 100 23 μm cellulosic membrane, molecular weight threshold: 13,000 2.4 4.1 36.6 73.2 83.7 100 46 μm cellulosic membrane, molecular weight threshold: 13,000 1.6 2.4 33.3 69.1 79.2 100 93 μm cellulosic membrane, molecular weight threshold: 13,000 0 0 17.2 43.9 49.0 69.7 25 μm cellulosic membrane, molecular weight threshold: 3500 0.9 2.7 11.6 67.0 75.9 100 50 μm cellulosic membrane, molecular weight threshold: 3500 0.9 1.7 4.3 49.9 56.8 80.0 20 μm polyethylene 0 0 3.0 - 22 * -

• * measured after 110 minutes

Example 2

Selectivity of release of tobacco components through membranes with different properties

membranes, from regenerated cellulose acetate dialysis hoses with varying thickness and varying molecular weight threshold produced were subjected to their selectivity for the transport of nicotine the membrane is tested while undesirable and possibly harmful Substances retained in the tobacco become.

to Investigation of selectivity The membrane was an experimental design, as in the example 1 is used.

When Membranes were regenerated cellulose acetate having a molecular weight threshold of 3500 and a thickness of 25.2 microns or a molecular weight threshold of 13,000 and a thickness of 23.2 microns or 46.4 microns used. Samples became 3, Pulled 30 and 90 minutes after the start of the experiment, and a UV spectrum from 200 nm to 900 nm was recorded for each sample.

As described above, the impurity index - IPI - was used as a measure of selective Release of nicotine introduced. The IPI is taken from the UV spectra recorded at 200 nm to 900 nm calculated and is considered the ratio the sum of peak heights, which are different from those of nicotine (i.e. thus undesirable and harmful Include substances) to the peak height defined by nicotine. All measurements are in the receiver chamber carried out, d. H. after permeation through the membrane in question. Of the IPI will be seen 3, 30 and 90 minutes after the start of the experiment above, measured. In such cases, where any additional Substances are added to the tobacco composition, for. B. sweeteners, Flavors, detergents, buffers, etc. are the peak heights of the same not usually included when calculating the sum of the peak height becomes as described above.

• IPI = F Peakhöhe anderer Substanzen/Σ Peakhöhe Nikotin

As mentioned above, a low IPI indicates that a large amount of nicotine is released through the membrane compared to the amount of undesired substances. Table 3 shows IPI values calculated for reference filter paper and for hydrophilic membranes of different molecular weight threshold and thickness. Table 3: Impurity Index (IPI) calculated for the Reference Filter Paper Membrane and Hydrophilic Regenerated Cellulose Acetate Membranes with different physical properties Time (min) Pollution Index (IPI) Membrane 1 Thickness: 25.2 μm Molar mass threshold: 3500 Membrane 2 Thickness: 23.2 μm Molar mass threshold: 13000 Membrane 3 Thickness: 46.4 μm Molar mass threshold: 13000 reference 3 0.9 0.75 1.05 1.64 30 1.17 1.24 1.17 2.91 90 1.26 1.35 1.25 3.35

• IPI = F peak height of other substances / Σ peak height nicotine

The Results of Table 3 show that the amount of undesirable Substances can be reduced almost threefold if one Cellulose membrane with a thickness and a molecular weight threshold in Table 3 is used compared to the Reference filter paper.

As in 1 is shown, the decrease in IPI is not only a result of a decrease in the overall release rate. Thus, release profiles relating to nicotine and using cellulose membranes with a molecular weight threshold of 13,000 are only a few percent lower than the release profile for the reference filter paper. Thus, the use of such membranes allows for release which allows the release of desirable substances (ie, nicotine) while retaining unwanted substances.

The results of Table 3 and the 1 indicate that the rate of release of undesirable substances increases as the membrane thickness decreases. However, it is important to point out that such an increase appears to correspond to the increase in release rate of nicotine, ie a decrease in membrane thickness does not result in a more pronounced release of undesired substances. In other words, the IPI value does not increase when the thickness of the membrane with a molecular weight threshold of 13,000 decreases from 46.4 μm to 23.2 μm.

Example 3

Optimization of membrane properties in terms of molecular weight threshold, thickness and low IPI values

example Figure 2 shows that no significant loss of membrane selectivity was observed becomes when the membrane thickness is reduced. Therefore, more became Studies done, about the relationship between membrane thickness, molecular weight threshold of the membrane and to study the amount of nicotine that is transmitted through the membrane by selected Data from Example 1 were analyzed.

Out 1 the maximum slope for each release profile was derived. The maximum slope. ie, percent nicotine release per unit time, dR / dt, represents the maximum flux of nicotine across the membranes (see Table 4). Table 4: Maximum flow values (% nicotine released per unit time, dR / dt) and time delay for different thicknesses of membranes with a molecular weight threshold of 3500, a molecular weight threshold of 13,000 and reference filters MW cut Thickness (μm) time delay (min) maximum nicotine flow (dR / dt) ∞ (reference bag) 0 1,250 Membrane with a molecular mass threshold of 13,000 23.2 0 1,205 46.4 0 1,144 92.8 0 0.637 Membrane with a molecular weight threshold of 3500 25.2 ≈ 50 1,250 50.4 ≈ 50 1,204

3 Figure 13 shows a graph of maximum flux as a function of membrane thickness for the cellulose membrane with a molecular weight threshold of 13,000. The figure shows that nicotine flux through the membrane approximates flow through a reference filter paper having virtually no barrier to nicotine diffusion a membrane thickness of about 10 microns.

A hydrophilic membrane with a molecular weight threshold of about 13,000 seems to no boundary layer / membrane effects or any large diffusion limitations for nicotine respectively. A thickness of about 10 microns gives a release profile comparable to the original ones commercially available wet snuff nonwoven bags is identical.

Example 4

Studies on nicotine intake at People from a new snuff composition

The Sensation of nicotine intake in humans when more commercially available Pouch snuff is applied compared to a new snuff composition according to the invention was examined.

In This study was the intake of nicotine from 1 g of snuff (SVENSKT SNUS, GOTHIATEK, General) in nonwoven original bags with the intake of nicotine from 1 g of snuff, which is regenerated in one Cellulose acetate membrane with a molecular weight threshold of 13,000 and a thickness of 23.2 microns is included compared.

The Study was conducted on subjects who were not snuff users. each Person ordered a dose of snuff under the lower lip, and they evaluated their observations regarding the feeling nicotine absorption in the bloodstream within certain time intervals.

The Sensation of nicotine intake in the bloodstream from the oral cavity was using a scale row from zero to five, where Zero indicated no sensation and five a very strong sense of Picture taken, which led to dizziness and nausea, evaluated.

The results of the study of nicotine intake are shown in Table 5. Table 5: Sensation of nicotine intake from commercially available bag snuff and from a snuff composition according to the invention person commercially available bag snuff moist snuff tobacco, which is arranged in a membrane with a molecular mass threshold of 13,000 Time (min) 0 2 4 6 8th 10 0 2 4 6 8th 12 16 Test person no. 1 0 0 2 3 5 5 0 0 1 2 3 4 5 Test person no. 2 0 0 1 4 5 5 0 0 1 3 4 4 5 Test person no. 3 0 0 1 3 4 5 0 0 1 2 3 4 4

Out those listed in Table 5 Results clearly show that the new snuff composition leads to a nicotine effect in subjects. Four minutes after the commercially available Bag snuff or the new snuff composition in the oral cavity were felt two of the subjects had a nicotine effect, giving a rating of one revealed. One of the subjects felt one degree higher Effect on commercially available Pouch snuff, compared to the new snuff composition.

The Results also show that the effect of nicotine intake is the new snuff composition is slightly delayed compared to the Sensation of nicotine intake from the commercially available Bag snuff. When using the commercially available bag snuff the feel Tested an effect that scored five at 8 to 10 minutes has been. When using the new snuff composition feel the subjects had the maximum effect after 12 to 16 minutes.

Claims (39)

A composition for use in the oral cavity, comprising a material selected from the group consisting of tobacco and Tobacco in combination with a tobacco substitute, wherein the material is encapsulated in a membrane material containing one or more Includes membranes, at least one of which is permeable to water and insoluble in water is, and wherein the impurity index of the composition, if it according to the present Description determined, at most 3.0, such as at most 2.75, at most 2.5, at most 2.0, at most 1.75, at most 1.5, at most 1.5 or at most 1.4, when measured after 90 minutes. Composition according to claim 1 for use as a snuff. A composition according to claim 1 or 2, wherein the composition is not in the form of a chewing gum. A composition according to any one of the preceding claims, wherein at least one membrane is a synthetic or semi-synthetic Membrane is. A composition according to any one of the preceding claims, wherein at least one membrane made of natural rubber. A composition according to any one of the preceding claims, wherein at least one membrane is a biocompatible membrane. A composition according to any one of the preceding claims, wherein the membrane is made of a polymeric material, such as one selected from the group cellulose acetate and derivatives thereof, carboxymethyl cellulose, Polycellulose esters, other cellulose derivatives, such as Ethylcellulose, propylcellulose, polyethylene, polypropylene, polystyrene, Polyvinyl chloride, polyvinyl acetal, polymers of methacrylates and Acrylates, natural rubber, polycarbonates, polyethylene terephthalate, Polyesters, polyamides and nylon. Composition according to any one of the preceding claims, wherein at least one of the membranes predominantly hydrophilic character. A composition according to any one of the preceding claims, wherein at least one of the membranes is predominantly hydrophobic in character. A composition according to any one of the preceding claims, wherein from the tobacco or tobacco substitute nicotine and / or a nicotine derivative, analogue, salt, solvate or mixture thereof is released. A composition according to claim 10, wherein the release is a controlled release. A composition according to claim 10 or 11, wherein the nicotine and / or nicotine derivative, analogue, salt, solvate or Mixture thereof is selected from the group consisting of nornicotine, Lobeline, methylanabasine, anabasine, nicotine hydrochloride, nicotine dihydrochloride, Nicotine sulfate, nicotine monotartrate, nicotine hydrogen tartrate, nicotine salicylate or nicotinic acid chloride monohydrate. A composition according to any one of the preceding claims which i) nicotine and / or a nicotine derivative, analogue, salt, solvate or mixture thereof in a sufficient amount and / or with one sufficient speed should release to a desired effect to enable and ii) withhold substances that normally cause side effects and / or such substances in a very small amount and / or should release at a very low speed. A composition according to any one of the preceding claims, wherein at least one of the membranes comprising the membrane material, a molecular weight threshold of about 500 to about 40,000, such as For example, about 500 to about 5000, about 800 to about 4000, about 1000 to about 3500, or about 2,000 to about 40,000, about 3,000 to about 30,000, about 5,000 to about 25,000, about 7,500 to about 20,000 or about 10,000 to about 20,000. A composition according to any one of the preceding claims, wherein at least one of the membranes comprising the membrane material, a thickness of about 2 to about 200 microns, such as about 5 to about 100 μm, about 7.5 to about 50 μm, about 7.5 to about 40 μm, about 7.5 to about 35 μm, about 7.5 to about 30 microns or about 7.5 to about 25 μm, having. A composition according to any one of the preceding claims, wherein at least about 50% by weight of the total nicotine content and / or Nicotine derivative, analog, salt, solvate or mixture thereof within at the most 60 min when released according to the release test described herein Is tested. A composition according to any one of claims 1 to 15, with at most 25% by weight of the total content of nicotine and / or nicotine derivative, -analogon, salt, solvate or mixture thereof within a maximum of 60 min when released according to the release test described herein Is tested. A composition according to any one of claims 1 to 15 or 17, wherein at least about 50 wt .-% of the total content of Nicotine and / or nico-tine derivative, -analogon, -salt, -solvate or Mixture of it within a maximum of 120 min when released according to the release assay described herein Is tested. A composition according to any one of the preceding claims, wherein the release of nicotine and / or nicotine derivative, analogue, salt, solvate or mixture thereof from the tobacco or tobacco substitute has the following characteristics: Time (min) Wt .-% of the total nicotine content released 0 from about 0 to about 20, such as from about 0 to about 15, or from about 0 to about 10; 3 from about 0.5 to about 40, such as from about 0.5 to about 35, from about 0.5 to about 30, from about 1 to about 25, or from about 1 to about 20; 30 from about 2 to about 65, such as from about 2 to about 60, from about 5 to about 60, from about 5 to about 55, from about 7.5 to about 65, or from about 10 to about 50; 90 from about 10 to about 100, such as about 10 to about 95, about 15 to about 90, about 20 to about 90, about 25 to about 85, about 30 to about 80, about 35 to about 80, or about 40 to about 80 ; 180 from about 40 to about 100, such as from about 45 to about 100, from about 50 to about 100, from about 55 to about 100, from about 60 to about 100, from about 65 to about 100, or from about 70 to about 100; and the release is determined as described herein. A composition according to any one of the preceding claims, wherein the release of nicotine and / or nicotine derivative, analogue, salt, solvate or mixture thereof from the tobacco or tobacco substitute has the following characteristics: Time (min) Wt .-% of the total nicotine content released 0 from about 0 to about 15; 3 from about 1 to about 25; 30 about 7.5 to about 55; 90 about 35 to about 80; 180 from about 65 to about 100; and the release is determined as described herein. A composition according to any one of the preceding claims, wherein the release of nicotine and / or nicotine derivative, analogue, salt, solvate or mixture thereof from the tobacco or tobacco substitute has the following characteristics: Time (min) Wt .-% of the total nicotine content released 0 from about 0 to about 10; 3 from about 1 to about 20; 30 from about 10 to about 50; 90 from about 40 to about 90; 180 about 70 to about 100, and the release is determined as described herein. A composition according to any one of the preceding claims, wherein the release of nicotine and / or nicotine derivative, analogue, salt, solvate or mixture thereof from the tobacco or tobacco substitute has the following characteristics: Time (min) Wt .-% of the total nicotine content released 0 from about 0 to about 10; 3 from about 1 to about 20; 30 about 30 to about 50; 90 from about 65 to about 90; and the release is determined as described herein. A composition according to any one of the preceding claims, wherein the tobacco from the leaves the plant family Solanaceae and the genus Nicotiana, such as Example Nicotiana tabacum and Nicotiana rustica, is processed. A composition according to any one of the preceding claims which Nicotine and / or a nicotine derivative, analogue, salt, solvate or a mixture thereof according to claim 12 together with tobacco in the form of snuff and / or a suitable filling substance includes. A composition according to any one of the preceding claims wherein the composition is further sweeteners, flavors, flavor additives, detergents, pH regulators, preservatives, buffers, release modifiers and / or fillers. A composition according to any one of the preceding claims, wherein the composition further comprises chemical compounds which enable and enhance the release of nicotine from tobacco, such as for example pH regulators, for example carbonates, buffers, oil, organic solvent and herbal extracts includes. A composition according to any one of the preceding claims, wherein the tobacco or tobacco substitute nicotine and / or a nicotine derivative, analog, salt, solvate or mixture thereof in one concentration from about 0% to about 30% by weight, such as about 0.5 to about 25 wt%, about 0.1 to about 20 wt%, about 0.1 to about 15 wt%, about 0.1 to about 10 wt%, about 0.1 to about 9 wt% or about 0.1 to about 8% by weight. A composition according to any one of the preceding claims, wherein the membrane material of at least two different types of Membranes, for example, in terms of thickness, molecular weight threshold, hydrophilic / hydrophobic nature and water permeability. A composition according to any one of the preceding claims, wherein the composition is a size and / or Form has that for the application is suitable under the upper lip of a human being. A composition according to any one of the preceding claims which contains a mixture of tobacco and a tobacco substitute. A composition according to any one of the preceding claims Use as a smoking substitute. A composition according to claim 30 or 31 for use for reducing nicotine craving and / or nicotine abstinence. Method for controlling the release of nicotine and / or a nicotine derivative, analog, salt, solvate or mixture of which tobacco and / or tobacco substitutes in the oral cavity, wherein the process involves encapsulating a material that is from the group selected is made of tobacco and tobacco in combination with a tobacco substitute consists in a membrane material comprising one or more Includes membranes, at least one of which is permeable to water and insoluble in water so that nicotine and / or a nicotine derivative, analogue, salt, solvate or mixture thereof in an amount and / or to be released at a sufficient speed, i) a desired one To make an impact and ii) substances that normally cause side effects and / or such substances in a very small amount and / or be released at a very low speed. Method for dispensing nicotine and / or a Derivative, analog, salt or solvate thereof to a person whose required, the method comprising applying a composition according to a the claims 1 to 32 in the oral cavity includes. Method of quitting smoking, wherein the method comprises applying a composition according to a the claims 1 to 32 in the oral cavity includes. Use of a composition according to one the claims 1 to 32 in the manufacture of a medicament for reducing the Nicotine Craving by applying the composition in the oral cavity. Use of a composition according to one the claims 1 to 32 in the manufacture of a medicament for reducing Side effects associated with smoking and / or colds of tobacco are by applying the composition in the oral cavity. Use of a composition according to one the claims 1 to 32 as an alternative to and / or replacement of tobacco smoking. A process for the preparation of a composition according to any one of claims 1 to 32, which process comprises encapsulating tobacco and / or tobacco substitute in a membrane material comprising one or more of comprises several membranes, of which at least one is water-permeable and water-insoluble.